Lupus: still a puzzle but more pieces falling into place

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Oct 22, 2002

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Lupus: still a puzzle but more pieces falling into place

Chicago, IL Lupus is " a baffling riddle with hidden answers and no cure, "

says a review of the disease on the American Medical Association website,

amednews.com, this month. But with novel treatments in trial, the

identification of new markers of the disease, and earlier diagnosis, " the

lupus puzzle has some promising pieces, " writes Kathleen F Phalen.

Overall, the piece is informative and balanced. Phalen notes that lupus is a

chronic, multisystemic inflammatory autoimmune disease " often affecting the

skin, joints, blood, and kidneys. " About 90% of patients are young women

between 15 and 45, and 70% of lupus cases are systemic lupus erythematosus

(SLE), the most severe and potentially fatal form of the disease, she says.

Earlier this year, the Centers for Disease Control reported a 60% increase

in lupus deaths since 1979, she notes, but " scientists discuss this figure

cautiously, fearing its misinterpretation. " She does not mention that the

majority of this increase in lupus-associated death is thought to be due to

increasing awareness of the disease, as reported by rheumawire. Outcomes

tend to be worse for minority patients, she adds, with a 70% increase in the

number of African American women dying from complications of lupus since

1980.

" For those with lupus, the immune system is not able to distinguish antigens

from its own cells. As a result, the system begins making autoantibodies.

There is speculation that environmental factors viral or bacterial

infections, UV light, prescription heart medication, antipsychotic drugs,

some antibiotics, stress, and certain hormones may be the cause. " Others

have pointed to a genetic predisposition, with several areas of chromosome 1

and the FAS gene having been linked with lupus. " Dozens of other genes are

currently under investigation, but scientists still do not know which genes

are associated with a greater likelihood of getting the disease. "

" We are at an all-time peak for lupus research. There is great cause for

optimism on a variety of fronts. "

Phalen has interviewed 5 rheumatologists for the piece and 1 expert in stem

cell transplantation their comments add authority to the piece. Many of

them are enthusiastic about the future of lupus research. Dr ph Ahearn

(Lupus Center of Excellence at the University of Pittsburgh Medical Center)

comments: " We are at an all-time peak for lupus research. There is great

cause for optimism on a variety of fronts. "

Difficulty in diagnosing lupus, but new tests emerging

Phalen homes in on the difficulty of diagnosing lupus, citing a study by the

Lupus Foundation of America that found that half of all lupus patients went

at least 4 years and saw 3 or more doctors before obtaining a correct

diagnosis. Those without the classic malar or " butterfly " rash are more

likely to be misdiagnosed, she notes. Dr Israeli Jaffe (Columbian

Presbyterian Eastside, New York) tells her: " It is a complicated diagnosis.

[However], today patients are diagnosed earlier. . . . That's good. It used

to be routine to end up on dialysis. The quality and duration of life have

improved. "

" It used to be routine to end up on dialysis. The quality and duration of

life have improved. "

There is no single test for lupus, Phalen observes. She mentions some of the

assays currently considered the " gold standard " for lupus, such as

antinuclear antibodies (ANA), serum C3, serum C4, and anti-double-stranded

DNA (anti-DNA), but notes that some patients will still be missed when only

these tests are used. The FDA has recently approved a new screening tool to

identify the 20% of lupus patients missed with older methods  the anti-SR

protein antibody assay, " a helpful biomarker for lupus since a majority of

patients produce antibodies to SR. " Also, a team at the University of

Pittsburgh is in the process of licensing a complement-based assay for

diagnosis and monitoring, she says.

Treatments " not ideal "

" Right now, treatments [for lupus] are not ideal, " Phalen writes. Most

commonly used are nonsteroidal anti-inflammatories, antimalarials such as

hydroxychloroquine or chloroquine, steroids, or cytotoxic agents such as

azathioprine or cyclophosphamide. But there are newer drugs in the pipeline,

including LJP 394 (La Jolla Pharmaceuticals), Genelabs's PrestaraTM

(formerly AsleraTM), eculizumab (ion Pharmaceuticals), and

LymphoStat-BTM (Human Genome Sciences).

Phalen makes no mention, however, of other products being tested in lupus,

including rituximab (Mabthera®, Hoffmann-LaRoche; Rituxan® Genentech),

anti-interleukin-10 products, mycophenolate mofetil (CellCept ®, Roche

Laboratories), and sex hormone manipulation for example, with

bromocriptine. But she does mention stem cell transplants, which " show great

promise for lupus patients. " Phalen notes this method of treatments is in

phase 3 multicenter trials for patients who have failed all other therapies.

At the end of the article are useful lists of SLE diagnostic criteria,

mortality statistics described as the " death toll " a list of new assays

and drugs " in the pipeline, " and a profile of a 29-year old lupus patient.

Compound holds promise for lupus?

Ann Arbor, MI Separately, US researchers have found that a

benzodiazepine-type compound may hold promise in the treatment of lupus. In

mice inbred to develop a disease resembling human SLE, Bz-423 significantly

reduced kidney inflammation, they report in the Oct 16 issue of the Journal

of Clinical Investigation [2]. The compound, " goes in and kills the bad

players but leaves the good players alone, " says the lead investigator Dr

D Glick (University of Michigan, Ann Arbor).

Bz-423, a 1,4-benzodiazepine lacking the propensity to cause drowsiness or

lead to addiction, sets off a chain of events that results in apoptosis.

" The results suggest that Bz-423, when administered appropriately, may have

a significant therapeutic potential for lupus, " says Glick. After completing

additional research on Bz-423, he plans to apply to the FDA for permission

to test the compound in humans.

Nainggolan

Cited sources

1. Phalen KF. Progress on lupus: New clarity for a baffling disease.

amednews.com Oct. 7, 2002. Available at:

http://www.ama-assn.org/sci-pubs/amnews/pick_02/hlsa1007.htm.

2. Blatt NB, Bednarski JJ, Warner RE, et al. Benzodiazepine-induced

superoxide signals B cell apoptosis: mechanistic insight and potential

therapeutic utility. J Clin Invest 2002; 110:1123-1132.